Investigation of atopic dermatitis in Greenland; distinct genotypes, phenotypes, and immunotypes
Grantee: Jacob Pontoppidan Thyssen, Consultant, PhD, DMSc, Assistant Professor, Department of Dermatology and Allergy, Herlev and Gentofte Hospital
Amount: DKK 5,078,619
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
The LEO Foundation supports this study aimed at improving diagnostic accuracy and treatment of Atopic dermatitis (AD) in Greenland, and to add to the general knowledge of AD.
The project’s hypothesis is that Inuit children with AD residing in Greenland display a population-specific prevalence, set of risk factors, phenotype, genotype, immunotype, and bacterial load. As part of showing this, it is intended to clarify potential Inuit-specific loss-of-function mutations in filaggrin gene (FLG) addressing the latitude dependent gradient in FLG mutation prevalence and its potential role in providing an evolutionary advantage.
In general, the settings in Greenland differ on many parameters from a conventional western society: The AD study population is expected to be different due to variation in living conditions, diet, climate, and genetic admixture. This is of particular importance to better examine and understand AD etiology and related risk factors and may hopefully provide a break-through in AD research.
In the project, the team will establish a large children cohort in Greenland to estimate prevalence, genotype, phenotype, immunotype, and risk factors for AD. By examining Inuit children with and without AD, compared with Danish children with AD, along with a cohort comparison from collaborating partners, the team will be able to examine whether phenotypic traits correlate with genotype, immunotype, ethnicity, or environmental factors, including gut and skin microbiomes.
The study offers an exclusive opportunity to examine AD in a homogenous small population in a secluded environment, and is foreseen to contribute to increased understanding of AD as an overall term, hereby its phenotype, genotype, immunotype, and specific risk factors. Both to understand better the pathogenesis of AD, and to improve and implement diagnostic tools for Greenlandic patients with AD.
Development of elastin-based biomaterials for wound healing
Grantee: Assistant Professor Andrea Heinz, LEO Foundation Center for Cutaneous Drug Delivery, Department of Pharmacy, University of Copenhagen
Amount: DKK 1,472,000
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
Wound healing is a complex biological process involving interaction of different types of cells, mediators, and components of the extracellular matrix.
In particular, re-epithelialization, closure of the wound by the epithelial cells, is a crucial step as it re-establishes skin continuity. The process, however, may be impaired in various pathological conditions such as diabetes, leading to the development of acute or chronic non-healing wounds.
This project, involving participants from Denmark, France, and Germany, aims to develop wound dressings based on novel polymer- and protein-based biomaterials capable of delivery of bioactive molecules. The basis will be elastin, an extracellular matrix protein with unique properties such as elasticity and biocompatibility.
In order to form the 3D scaffolds needed for wound dressings, state-of-the-art electrospinning will be utilized and hydrogels will be prepared by in vitro cross-linking of elastin-based peptides. The conditions of preparation will be tuned to produce a biomaterial of desired mechanical properties, which will then be characterized physio-chemically using a range of analytical techniques.
Addition of bioactive peptides and growth factors will allow for stimulation of wound healing. The materials will be tested in vitro using human fibroblast cell cultures and in vivo using animal wound models.
p14-ARF in familiar melanoma: a promising target that acts as a melanocyte guardian
Grantee: Elena Papaleo, Junior Group Leader, Computational Biology Laboratory, Danish Cancer Society Research Center, Copenhagen
Amount: DKK 1,300,000
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
Melanoma is one of the most aggressive skin cancers and its incidence in Denmark has increased over the last decade, becoming the most frequent type of cancer in young women. Despite recent discoveries on melanoma mechanisms, the prognosis for the patient is still poor and extensive research efforts are needed to clarify the molecular mechanisms involved and identify new therapeutic targets.
The outcome of this project has the potential to join these efforts by advancing the comprehension of metabolic reprogramming which forms the basis for aggressiveness and resistance to treatments in familial melanoma.
The most common mutations in familial melanoma are found in genes encoding the proteins INK4A and p14-ARF (ARF), and the basis for the project is the newly discovered function of ARF to act as guardian in human melanocytes by maintaining low levels of superoxide in conditions of mitochondrial dysfunction, protecting the melanocytes from reactive oxygen species.
The protective mechanisms mediated by ARF rely on its physical interaction with BCL-xL, a trans-membrane molecule, and this interaction could be disrupted by germline mutations of ARF. The understanding of the interaction mode and how mutations interfere with them is a fundamental step to target the BCL-xL/ARF complex for therapeutic purposes.
Carried out in a cross-disciplinary environment at the Danish Cancer Society Research Center, the project brings together experts in cellular cancer biology, structural biology, and bioinformatics. The team has access to many supercomputing facilities to speed up the data acquisition of the envisioned time-consuming simulations.
Regulation of IL-22 secretion by vitamin D in relation to Atopic Dermatitis
Grantee: Carsten Geisler, Professor and Head of Department, Department of Immunology and Microbiology, University of Copenhagen
Amount: DKK 2,779,900
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
Atopic dermatitis (AD) is a common skin disorder affecting up to 25% of children and 3% of adults. Currently, no good treatment options exist and AD has a large impact on quality of life.
The skin of AD patients’ is characterized by inflammation caused by infiltration of both dendritic cells (DCs) and T cells leading to among other highly itching plaques. Furthermore, AD lesions are prone to infections due to a decreased barrier function of the skin.
A newly described T cell subset, Th22 cells, is suggested as a main driver of AD with an increased infiltration of both Th22 and Tc22 cells correlating with disease severity.
Treatment with narrow-band ultraviolet B radiation (NB-UVB) has proven effective in reducing the disease-scoring index of AD patients. This is accompanied by a suppression of the Th2/Th22 axis and there are ongoing clinical trials with blocking antibodies against IL-22 for AD treatment.
UVB radiation of skin is known to initiate the production of vitamin D with its potent immunomodulatory properties, and it shows that activation of human CD4+ T cells leads to a secretion of IL-21 and IL-22 – a secretion that therefore can be inhibited by vitamin D.
This project will investigate the effects of vitamin D in a physiologically relevant in vitro differentiation system of CD4+ T cells towards the Th22 lineage, targeting a better understanding of the interplay between the developments of Th22 cells in relation to AD.
Furthermore, the project will potentially provide a basis for the understanding of the molecular and cellular events in AD, and the possible symptom alleviation of patients following topical treatment with vitamin D analogues.
The spatial composition and distribution of the cutaneous microbiota in atopic dermatitis and healthy skin
Grantee: Professor Thomas Bjarnsholt DMSc, PhD, Costerton Biofilm Center, Department of Immunology and Microbiology, and Department of Clinical Microbiology, University of Copenhagen
Amount: DKK 2,857,565
Grant category: Research Grants in open competition
Year: 2017
Geography: Denmark
In this study, Dr Bjarnsholt looks at skin microbiota and expects to illuminate consistencies and differences between atopic dermatitis and healthy skin. He will do so with focus on the cutaneous microbial composition and spatial distribution in the different layers in AD relative to healthy skin.
The skin microbiota is recognised to significantly impact human health but remains incompletely characterised in the pathogenesis of common cutaneous conditions such as AD. Understanding the three-dimensional distribution of bacteria within the skin may provide relevant insights regarding transition from healthy to diseased skin.
This study will compare the distribution and composition of the commensal, skin microbiota in dry, moist and sebaceous environments as they relate to early onset in AD patients relative to healthy volunteers.
Tape strips and sub-divided skin biopsies will be sampled and analysed by three informative, supplementary methods, i.e. cultivation, Confocal Laser Scanning Microscopy (CLSM) and Next Generation Sequencing (NGS).
This is foreseen to show how the microbiota changes in immediately adjacent regions of tissue among diseased and healthy individuals. In addition, generation of high-resolution, 3D images by confocal microscopy will allow visualisation and confirmation of the molecular and culture results.
Influence of microbes on development of skin diseases
Grantee: Anders Johannes Hansen, PhD, Associate Professor, University of Copenhagen, Denmark, Robert Gniadecki, MD, Professor, Dermatology Department, Bispebjerg Hospital, Copenhagen, Denmark, Kim Holmstrøm, R&D Manager, Department of Biomedical Technology, Bioneer A/S, and Nicola Segata, PhD, Assistant Professor and Principal Investigator, Computational Metagenomics, CIBIO, University of Trento, Italy
Amount: DKK 5,035,000
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark, Italy
By combining new data from the human skin microbiome with existing knowledge of pathophysiology and clinical phenotypes of Atopic Dermatitis, AD, Actinic Keratosis, AK and non-melanoma skin cancer, the team will seek to establish a novel understanding of these diseases.
Recent microbiome analyses have revealed that mammalian body surfaces are colonized by vast numbers of bacterial communities, which motivates the exploration of the role of the microbiota in normal and diseased skin. There are indications that the skin microbiome plays a key role in both inflammatory skin disease and non-melanoma skin cancer.
The vision for the team’s research endeavours is to explore the microbiome for the identification of new targets for treatment, and for the development of improved treatment modalities for patients with AD, AK and non-melanoma skin cancer.
The team’s explorations will potentially also lead to the development of better and more specific and sensitive diagnostic and prognostic methods for monitoring skin disease.
The Danish-Italian team will work from a unique microbiome discovery platform established at the University of Copenhagen (UCPH) within the GenomeDenmark Cancer & Pathogen project. The platform utilizes procedures enriching various types of microbes combined with state of the art DNA and RNA sequencing and bioinformatics data analysis.
Skin barrier dysfunction and thymus size during the first year of life as predictors for atopic dermatitis
Grantee: Jacob P. Thyssen MD PhD DmSci, Trine Danvad Nilausen MD, Lone Skov MD PhD DmSci, Dep. Dermatology and Allergology, Herlev-Gentofte Hospital, Hellerup, Denmark, Caroline Ewertsen MD PhD, Department of Radiology, Rigshospitalet, Copenhagen, Denmark, Charlotte Bonefeld PhD, Department of International Health, Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, Pal Szecsi MD DmSci, Department of Clinical Biochemistry, Herlev-Gentofte Hospital, Hellerup , Denmark, Sanja Kezic PhD, Coronel Institute, AMC, University of Amsterdam, The Netherlands, and Christoph Riethmüller PhD, nAnostic Institute, Centre for Nanotechnology, University of Münster, Germany
Amount: DKK 2,558,500
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark, Germany, Netherlands
The study is foreseen to increase the understanding of the skin barrier and immune system in atopic dermatitis.
Through international collaboration with scientists who perform state of the art and pioneering analyses on skin samples as well as national collaboration with immunologists and radiologists, the team will seek to evaluate non-invasive and easily collectable biomarkers that can predict the risk for atopic dermatitis.
The study has the potential to provide insight in atopic dermatitis pathogenesis and the value of promising pre-atopic dermatitis biomarkers that indicate both inflammation and skin barrier barriers dysfunction. This could be used to develop an algorithm that can better predict the onset of atopic dermatitis.
The team’s work may thus substantially increase the understanding of skin biology in neonates, both normal and diseased. The study will also provide a basis for not only future large-scale observational studies, but also randomised controlled studies evaluating the efficacy of preventive skin barrier restoration or anti-inflammatory treatment in selected groups, potentially reducing the incidence and complications of the most common skin disease in childhood.
Developing deep understanding of atopic dermatitis
Grantee: Joel Dudley, PhD, Director of Biomedical informatics, Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA, and Jeanne Duus Johansen, MD, DMSc, Director National Allergy Research Centre, Department of Dermato-Allergology, Gentofte Hospital, University of Copenhagen, Denmark
Amount: DKK 11,100,000
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark, USA
Atopic dermatitis (AD) and hand dermatitis are heterogeneous disease entities and there has yet to be developed a good understanding of their many different clinical aspects. Thus it remains extremely challenging to provide patients with better treatment outcomes and prognosis.
A newly formed team of scientists at Gentofte Hospital in Copenhagen and Mount Sinai in New York has set out to change this.
“Next generation sequencing and advanced bioinformatics technologies give us powerful new opportunities to explore and understand the molecular pathophysiology of atopic dermatitis and hand dermatitis,” said Dr. Joel Dudley, Director of Biomedical informatics at Icahn School of Medicine, Mount Sinai in New York.
“It is a study that has not previously been performed, and we expect to make a breakthrough in the understanding, classification and treatment of these skin diseases. We hope to improve our knowledge and understanding of the molecular basis of atopic dermatitis and hand dermatitis and their relation to clinical features. Consequently, we also hope to pave the way for improved opportunities for managing and preventing disease,” said Dr. Jeanne Duus Johansen from the Department of Dermato-Allergology at Gentofte Hospital.
She and Joel Dudley will lead a trans-Atlantic team of researchers working with high-throughput, genome-wide profiling of multiple of the ‘–omics’ modalities, including genome, transcriptome, epigenome, and microbiome.
The goal is to develop a deeper understanding of how the molecular manifestation of the heterogeneous diseases correlates with clinical variables such as onset of disease and treatment outcomes. The technologies employed by the team can provide comprehensive molecular profiles that can enhance the understanding of the system-wide mechanics and properties of complex biological systems.
Dudley’s team will integrate the ‘-omics’ data sets to clarify the complex biological mechanisms underlying disease. They will do so by connecting molecular profiles with clinical data to identify molecular surrogates of drivers of important clinical features of disease.
The study will build on previous efforts to assemble and characterise a Danish cohort of individuals affected by AD in adulthood and/or hand dermatitis. The proposed study will add important new dimensions of molecular information that will enable new insights into molecular mechanisms and features of disease. Furthermore, the team sees that an incorporation of molecular measures, namely microbiome and epigenome, may offer insight into environmental correlates or determinants of disease.
Finally, the team foresees that the data and results generated may serve as an important new asset to the AD and dermatology research communities.
“We believe that the data and results generated by our study will enable new research directions and insights into AD and dermatological disease. Furthermore, we believe that such future insights would be enabled by the unique availability of the proposed comprehensive multi-omics data set integrated with comprehensive clinical data and assessment of a large patient cohort,” said Dr. Jeanne Duus Johansen.
Cardiovascular risk in psoriasis – meeting a profound clinical need
Grantee: Joel Dudley, PhD, Director of Biomedical informatics, Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai, New York, USA, and Peter Riis Hansen, MD, DMSc, PhD, Consultant (invasive cardiology), Associate Professor, Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark
Amount: DKK 13,100,000
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark, USA
Cardiovascular diseases (CVD), such as myocardial infarction and stroke, are leading causes of death globally. Independent of traditional risk factors, however, psoriasis patients run an increased risk of CVD, adding considerably to morbidity and mortality for this large patient group.
“Inflammation has been proposed as a part of the explanation for the association between psoriasis and CVD. However, when we look at the underlying pathophysiology and molecular drivers of this connection, they are unclear. It is also unresolved whether treatment responses for psoriasis alter the course of CVD. To us, this suggests that the connection with inflammation might be more complex than currently appreciated,” said Joel Dudley, Director of Biomedical informatics at Icahn School of Medicine, Mount Sinai in New York.
Together with Peter Riis Hansen, Department of Cardiology, Gentofte Hospital, University of Copenhagen, Denmark, Dudley will lead a team focused on developing a much needed understanding between the molecular mechanisms of psoriasis and the increase in CVD comorbidity. Understanding these complex interactions between skin and cardiovascular health will lead to insights for future preventive treatments and improved prognosis.
The team will employ an array of modern high throughput technologies to bring together information about genetics, immunology, local gene expression, microbiomes, and more standard clinical measures to develop an unprecedented map of factors impacting cardiovascular health in psoriatic patients.
“We will apply sophisticated bioinformatics and network biology techniques to integrate the data and develop a disease network model that will enable both discovery and testing of novel hypotheses concerning biomarkers and pathogenic mechanisms. We believe that this disease network model will serve as a powerful and unprecedented resource for the dermatology, cardiology, and immunology research communities,” said Peter Riis Hansen.
More specifically, the model may facilitate the re-interpretation of data from previous studies and clinical trials, be queried by scientific and clinical investigators to evaluate novel clinical and molecular hypotheses, and inform new understanding of fundamental molecular mechanisms underlying the interplay between skin biology, immune function, and the immune-metabolic-cardiovascular axis.
The resulting disease network model may also uncover molecular mechanisms contributing to increased CVD risk in other immune disorders, such as rheumatoid arthritis, atopic dermatitis, and inflammatory bowel disease.
“We believe that the data generation activities alone would provide tremendous value to the research community, and that developments in data analysis and bioinformatics has the potential to increase exponentially our understanding of molecular mechanisms underlying CVD risk in inflammatory skin disease,” said Peter Riis Hansen.
Skin barrier function is first line of defence – Epidermal T cells dynamic, interplay and function
Grantee: Charlotte Menné Bonefeld, Associated Professor, Department of Immunology and Microbiology, University of Copenhagen
Amount: DKK 2,385,900
Grant category: Research Grants in open competition
Year: 2016
Geography: Denmark
The skin provides the first barrier of defence between the body and the environment. It is one of the largest organs of the human body and is constantly being exposed to pathogens and environmental triggers.
The outermost layer of the skin is the epidermis and it consists of a variety of both immune and non-immune cell types. Among the immune cells within epidermis are the T cells. One of the important characteristics of T cells is that they can develop into memory T cells following their activation.
Experimental work is often done with mice, but experience shows that there is difference between T cells in humans and mice epidermis – a difference that until recently has been thought related to species diversity.
Recent findings, however, have shown that environmental triggering factors, such as microorganisms or chemical irritants, lead to a dynamic shaping of the type of T cells present in the epidermis. Based on these discoveries, the team led by Charlotte Menné Bonefeld has hypothesised that the difference between T cells in human and mice epidermis are not mediated by species differences, but rather by difference in skin exposure to microorganisms and chemicals that occurs early and throughout the whole life.
Therefore, the team will investigate i) the similarities and differences of T cells in human and mice epidermis, ii) the effect of allergen and infection agents on the phenotype and activity of epidermal T cells and iii) the interplay between epidermal immune cells forming the immunological barrier properties of the skin.
Answering these questions will be crucial for developing better treatments for inflammatory skin diseases as it is very likely that these mechanisms play a central role in the pathogenesis of several inflammatory skin diseases like allergic contact dermatitis, atopic dermatitis and psoriasis.